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Review

published: 16 April 2018


doi: 10.3389/fnut.2018.00025

Antimetabolic Effects of Polyphenols


in Breast Cancer Cells: Focus on
Glucose Uptake and Metabolism
Elisa Keating1,2 and Fátima Martel1,3*
1
 Department of Biomedicine, Unit of Biochemistry, Faculty of Medicine, University of Porto, Porto, Portugal, 2 CINTESIS,
Center for Research in Health Technologies and Information Systems, University of Porto, Porto, Portugal, 3 Instituto de
Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal

In the last years, metabolic reprogramming became a new key hallmark of tumor cells.
One of its components is a deviant energetic metabolism, known as Warburg effect—an
aerobic lactatogenesis—characterized by elevated rates of glucose uptake and con-
sumption with high-lactate production even in the presence of oxygen. Because many
cancer cells display a greater sensitivity to glucose deprivation-induced cytotoxicity than
normal cells, inhibitors of glucose cellular uptake (facilitative glucose transporter 1 inhib-
itors) and oxidative metabolism (glycolysis inhibitors) are potential therapeutic targets
Edited by:
in cancer treatment. Polyphenols, abundantly contained in fruits and vegetables, are
Fatima Baltazar,
University of Minho, Portugal dietary components with an established protective role against cancer. Several molecular
Reviewed by: mechanisms are involved in the anticancer effect of polyphenols, including effects on
Ulkan Kilic, apoptosis, cell cycle regulation, plasma membrane receptors, signaling pathways, and
University of Health Sciences, Turkey
Sandrine Silvente-Poirot,
epigenetic mechanisms. Additionally, inhibition of glucose cellular uptake and metabo-
Institut National de la Santé lism in cancer cell lines has been described for several polyphenols, and this effect was
et de la Recherche Médicale
shown to be associated with their anticarcinogenic effect. This work will review data
(INSERM), France
Odilia Queiros, showing an antimetabolic effect of polyphenols and its involvement in the chemopreven-
Instituto Superior de Ciências tive/chemotherapeutic potential of these dietary compounds, in relation to breast cancer.
da Saúde Norte, Portugal

*Correspondence: Keywords: polyphenols, Warburg effect, glucose uptake, glycolysis, breast cancer
Fátima Martel
fmartel@med.up.pt

INTRODUCTION
Specialty section:
This article was submitted Breast cancer is the second most common cancer worldwide, after lung cancer, and it is the most
to Clinical Nutrition, common cancer among women (1). This type of cancer is the fifth cause of death from cancers in
a section of the journal both sexes and the first in women (1). Nevertheless, 5-year survival rates in breast cancer patients are
Frontiers in Nutrition
very high in high-income countries, reaching 80% and decreasing to 40% in low-income countries,
Received: 15 January 2018 mainly because of reduced availability of screening strategies (1, 2). The widespread adoption of
Accepted: 27 March 2018
screening mammography together with the use of post-menopausal replacement hormonal therapy
Published: 16 April 2018
accounts for the increased incidence of breast cancer observed since the 1970s (3), meaning that
Citation: this disease is detected earlier and is now more preventable than ever.
Keating E and Martel F (2018)
Despite the overall promising statistics regarding breast cancer, global efforts must be under-
Antimetabolic Effects of Polyphenols
in Breast Cancer Cells: Focus on
taken in order to eradicate breast cancer as a chronic disease and to reduce mortality, treatment-
Glucose Uptake and Metabolism. associated morbidities and, importantly, the overwhelming emotional and economic burden
Front. Nutr. 5:25. associated with this disease. The Lancet Oncology Commission has very recently published a
doi: 10.3389/fnut.2018.00025 report listing cancer research priorities for the near future (4). Cancer research, management, and

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Keating and Martel Polyphenols and Breast Cancer

drug discovery during the last decades focused particularly on effect, which relies on their known antioxidant, anti-inflammatory,
the discovery of new molecular targets and in the refinement of antiproliferative, pro-apoptotic, and antiangiogenic potential. In
lead compounds, and these research areas are still part of that addition to this, many polyphenols have been shown to inhibit
list of priorities in the United States (4). several steps in energy metabolism of cancer cells, namely glucose
Cancer cell energy metabolism is an important hallmark of can- uptake and glucose metabolic enzymes. This paper intends to
cer (5) with deep interest as a molecular target for cancer therapy. review the literature regarding the known antimetabolic effects
Cancer cells, when compared with normal cells, are dependent of polyphenols, particularly in breast cancer cells.
in much higher rates of glucose uptake and, unlike normal cells,
they exhibit an apparently energy inefficient metabolic switch in POLYPHENOLS AND CANCER
which they deviate glycolysis oxidation to lactate production even
when oxygen is available (see “Glucose Uptake and Metabolism Polyphenols, also called phenolic compounds, constitute a
in Normal and Cancer Cells” for further details). This process, heterogeneous and large family of natural compounds widely
previously named “aerobic glycolysis” or the Warburg effect (5), distributed in plants. These compounds are products of plant
but which we believe to match better an “aerobic lactatogenesis” secondary metabolism and act by protecting against stressors
(6), is believed to be a cancer cell fingerprint that can be used as (e.g., UV light, pests) and in reproduction, by conferring colors
a specific molecular therapeutic target (Figure  1). Therapeutic to plants and consequently attracting insects for pollination (8).
approaches directed toward this fingerprint will likely cause less Polyphenols may be divided into classes and subclasses according
adverse side effects thus contributing to reduce treatment-associ- to their chemical structures (Figure 2).
ated morbidities. Many compounds targeting energy metabolism Polyphenols are an integral part of the human diet, and fruit
are currently in trial or are approved as therapeutic agents against and beverages such as tea and red wine represent the main
cancer (7). These include specific inhibitors of cancer-specific sources of these compounds (13). For example, berry fruits are
mutant isocitrate dehydrogenase (IDH 1 and/or IDH2), of the rich sources of anthocyanins, citrus fruits of flavanones, and
monocarboxylate transporter, critical for cancer cell nourishment apples of flavonols. Tea is a reach source of flavanols and coffee of
using lactate, of the pyruvate dehydrogenase complex or of the hydroxycynnamic acids (8).
mitochondrial complex I (7). Research in polyphenols continues to increase, as dem-
Current molecular targets for breast cancer therapy rely onstrated by the continuous increase in the number of papers
mainly on the expression of hormone receptors (estrogen and/or regarding these compounds. A PubMed search with the term
progesterone receptors) and of human epidermal growth factor “polyphenols” shows that scientific production regarding this
receptor 2 (HER2). In each case, the expression of these recep- subject almost triplicated in the last decade (637 papers in 2007
tors determines whether the patient should receive endocrine up to 1,812 papers in 2017).
(hormone receptor-positive cases) and/or anti-HER2 antibody Much of the scientific interest in the study of polyphenols
(HER2-positive cases) therapy (3). arises from studies showing that polyphenol-rich foods and bev-
Polyphenols, a heterogeneous family of natural compounds erages protect against chronic diseases including type 2 diabetes
widely distributed in plants, are known to have a cancer-protective and cardiovascular diseases (8), obesity (4), and cancer (8, 14, 15).

Figure 1 | Comparison between glucose metabolism in normal and cancer cells. 1—oxidative phosphorylation. 2—anaerobic glycolysis. 3—aerobic glycolysis
(aerobic lactatogenesis).

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Keating and Martel Polyphenols and Breast Cancer

inflammation, expression of cell receptors or transcription fac-


tors, and synthesis of hormones. Recent reviews are available
for detailed information (6, 14, 15) on these subjects. Molecular
mechanisms involved in the anticancer effect of polyphenols in
relation to breast cancer include interference with redox balance
(acting either as antioxidant or pro-oxidant, they exert chemo-
preventive and antitumoral effects, respectively), cell cycle arrest,
pro-apoptotic, autophagy activation, anti-inflammatory effect
(inhibition of NF-kB, COX-2, and LOX), antiestrogenic effect,
changes in ER expression, aromatase modulation, and interfer-
ence with HER2 signaling (14).
Additionally, polyphenols may also interact with the microbi-
ome: not only does gut microbiota transform many polyphenols,
thus modulating their bioactivity, but also, polyphenols are known
to modulate microbiome composition with a putative impact in
human health (16). For example, Paul et  al. have very recently
gathered evidence that consumption of a genistein-enriched
diet increased the abundance of members of Lachnospiraceae
and Ruminococcaceae short-chain fatty acid (SCFA)-producing
families, in microbiota of humanized mice (17). This was accom-
panied by a reduction in breast tumor size and an increase in
breast tumor latency (period of time free of tumor, after injection
of MDA-MB-231 breast cancer cells). The authors hypothesize
that SCFA produced by the genistein-induced microbiota strains
would epigenetically modulate tumor biology (17). Information
on epigenetic regulation induced by gut microbiota can be found
in a recently published review (18).
Also, polyphenols may exert cancer-protective effects directly
through epigenetic modifications. Indeed, these dietary com-
pounds have been shown to interfere with the three major epige-
netic mechanisms, i.e., DNA methylation, histone modification,
and non-coding RNAs, and these effects will also contribute to
their anticancer potential (19–22), for example, in the restoration
of the expression of tumor suppressor genes (6).
Finally, it has becoming increasingly recognized that poly-
phenols may also interfere in glucose uptake and metabolism in
cancer cells (Figure 3A). In this work, we will review the existing
data showing that polyphenols act as metabolic antagonists for
breast cancer cells.

GLUCOSE UPTAKE AND METABOLISM


IN NORMAL AND CANCER CELLS
Glucose is the primary energy source for many mammalian
cells. This sugar can be either obtained from our diet or de novo
synthesized in organs such as the liver and the kidney. Due to
its low lipophilicity, transfer of glucose across biological mem-
branes requires specific carrier proteins. In mammalian plasma
membrane, two distinct families of transporters mediate glucose
Figure 2 | Classification of polyphenols according to their structures. transfer: the sodium-dependent glucose co-transporters (SGLTs)
Numbers in parenthesis represent the total number of compounds known and the facilitative glucose transporters (GLUTs).
in each sub-class. Adapted from Ref. (9–12). The SGLT (gene symbol SLC5A) family of transporters are
secondary active transporters that mediate glucose transport
against its concentration gradient, coupled with sodium trans-
Regarding their anticancer effect, polyphenols have shown port down its concentration gradient The Na+-electrochemical
bioactivity in several cancer molecular features, namely redox gradient is provided by the Na+–K+ ATPase pump (23). SGLT1,
balance, cell proliferation, apoptosis, autophagy, angiogenesis, the first member of this family to be cloned, is a high-affinity

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Keating and Martel Polyphenols and Breast Cancer

Figure 3 | Effect of polyphenols on glucose cellular uptake and enzymes involved in glucose metabolism. GLUT, glucose transporter; PFK, phosphofructokinase-1;
fructose-6-P, fructose-6-phosphate; fructose-1,6-BP, fructose-1,6-biphosphate; ROS, reactive oxygen species; GAP, glyceraldehyde-3-phosphate; DHAP,
dihydroxyacetone phosphate; GLO1, glyoxalase-1; GLO2, glyoxalase-1; UGDH, UDP-glucose dehydrogenase; PI3K, phosphoinositide 3-kinase; PIP3,
phosphatidylinositol 3,4,5-trisphosphate; Akt, protein kinase B; HIF-1α, hypoxia-inducible factor 1- α. (A) General antimetabolic effects of polyphenols,
(B) naringenin effect, (C) resveratrol effect, (D) polyphenol effect on GLO1, and (E) polyphenol effect on UGDH.

Table 1 | The sodium-dependent glucose co-transporter (SGLT) and facilitative glucose transporter (GLUT) family of GLUTs.

Family Isoform Gene name Tissue distribution Substrate specificity

GLUT GLUT1 SLC2A1 Ubiquotous (brain, red blood cells, colon, placenta) Glucose/galactose
GLUT2 SLC2A2 Intestine, liver, kidney, beta cells Glucose/fructose/galactose
GLUT3 (GLUT14) SLC2A3 Brain, testis, kidney, placenta Glucose/galactose
GLUT4 SLC2A4 Skeletal and cardiac muscle cells, adipose cells Glucose
GLUT5 SLC2A5 Intestine, kidney, muscle, brain, testis Fructose
GLUT6 SLC2A6 Brain, spleen Glucose
GLUT7 SLC2A7 Small intestine, colon, testis, prostate, liver Fructose, glucose
GLUT8 SLC2A8 Testis, brain, fat, liver, spleen Glucose/fructose
GLUT9 SLC2A9 Kidney, liver, placenta, colon Fructose/glucose
GLUT10 SLC2A10 Heart, lung Glucose
GLUT11 SLC2A11 Muscle, heart, placenta, kidney, pancreas, fat Glucose
GLUT12 SLC2A12 Heart, prostate Glucose/fructose
SGLT SGLT1 SLC5A1 Intestine, trachea, kidney, heart, brain, testis, prostate Glucose/galactose
SGLT2 SLC5A2 Kidney, brain, liver, thyroid, muscle, heart Glucose
SGLT3 SLC5A4 Intestine, testis, uterus, lung, brain, thyroid Glucose
SGLT4 SLC5A9 Intestine, kidney, liver, brain, lung, trachea, uterus, pancreas Glucose
SGLT5 SLC5A10 Kidney Glucose/galactose
SGLT6 SLC5A11 Kidney, brain, intestine Glucose

glucose transporter found primarily in the apical membrane The GLUT (gene symbol SLC2A) family of facilitative
of enterocytes in the small intestine, with very small amounts transporters mediate glucose transport down its concentration
detectable in the kidneys and the heart (22). SGLT2 is the major gradient. This family of transporters includes fourteen members:
co-transporter involved in glucose reabsorption in the kidney, GLUT1 to GLUT12, GLUT14 and the H+/myo-inositol trans-
and SGLT2 inhibitors are a novel class of agents used to treat type porter (HMIT) (21) (Table 1). GLUT1 is present in many tissues
2 diabetes (24) (Table 1). and is responsible for basal glucose uptake in most tissues (25).

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Keating and Martel Polyphenols and Breast Cancer

GLUT4, the insulin-responsive GLUT, is found in heart, skeletal GLUT5 was also described (34, 37, 43). Moreover, expression of
muscle and adipose tissue, and constitutes the major cellular GLUT4 (42, 44–47) and insulin-stimulated glucose uptake were
mechanism that diminishes blood glucose when carbohydrates also found in some breast cancer cell lines (48–50). Although not
are ingested (26). In healthy mammary glands, GLUT1 is the much is known concerning the involvement of GLUT4 in cancer
predominant isoform expressed, but GLUT8 expression was also biology (51–53), downregulation of GLUT4 expression in the
reported (27). breast cancer cell lines MCF-7 and MDA-MB-231 cells impaired
Besides the ATP necessary to maintain normal cellular pro- basal glucose uptake, promoted metabolic reprogramming from
cesses, highly proliferating tumor cells must also produce the lactate production to oxidative phosphorylation and decreased
extra ATP necessary to support three basic needs of these cells: cell proliferation and viability, strongly suggesting the participa-
maintenance of energy status, increased biosynthesis of macro- tion of this transporter in basal glucose uptake in breast cancer
molecules such as proteins, and maintenance of cellular redox cell lines with different degrees of malignancy and differentiation
status (28). It is now recognized that tumor cells reprogramme (54). Finally, GLUT12, which was proposed as a second insulin-
their metabolic pathways in order to meet this extra energetic responsive GLUT (55, 56), was also found to be expressed in
demand necessary for tumor proliferation (28). One important MCF-7 cells (34, 57).
metabolic change observed in tumor cells is the Warburg effect, Glucose transporter-1 gene expression correlates with cancers
which consists in a shift from ATP generation in the mitochondria of higher grade and proliferative index and lower degree of dif-
through oxidative phosphorylation to cytosolic ATP generation ferentiation (35) and with increased malignant potential, inva-
through glycolysis with lactate production, even under normal siveness, and, consequently, poorer prognosis (41). GLUT1 has
oxygen concentrations (28, 29). So, distinctly from normal cells, thus been proposed as an oncogene (34, 37, 38). Besides GLUT1,
many tumoral cells derive a considerable amount of their ATP expression of other two GLUTs also present in breast cancer
by converting most incoming glucose to lactate (6) (Figure 1). cells, namely GLUT3 and GLUT12 (see above), is also associated
This “aerobic glycolytic” (which we think should better be named with a poor prognosis (34, 37). This demonstrates the extreme
“aerobic lactatogenic”) phenotype of tumor cells favors cell prolif- importance of glucose cellular uptake and GLUT transporters for
eration, and thus cancer progression, because (a) it generates high tumor cell survival and proliferation.
levels of glycolytic intermediates that contribute to biosynthetic Apart from GLUT family members, SGLT1 and SGLT2 overex-
pathways (5), and (b) it increases glucose metabolism, which pression has also been found in various cancers, such as pancreas,
appears to compensate for excess metabolic production of ROS prostate, lung, liver, and lymph node cancer (58). However, SGLT
in cancer cells (30). Aerobic glycolysis is now considered a key expression levels in breast cancer cells have not been determined.
feature in cancer and has recently taken place in the famous
‘‘Hallmarks of cancer’’ described by Hanahan and Weinberg (5).
ATP production by “aerobic lactatogenesis” is far more rapid EFFECT OF POLYPHENOLS ON GLUCOSE
than ATP production by oxidative phosphorylation, but it is far TRANSPORT IN BREAST CANCER CELLS
less efficient. Indeed, up to 38 mol of ATP per mole of glucose is
obtained when glycolysis is followed by the Krebs cycle and oxi- Polyphenolic compounds are known to have anticancer effects,
dative phosphorylation (31), but only 2 mol of ATP per mole of mediated by a plethora of cellular effects (see above). Interestingly,
glucose is obtained when glycolysis is followed by lactate produc- polyphenols have been found to interfere with both GLUT and
tion, by oxidation of pyruvate mediated by lactate dehydrogenase SGLT transporters in several tissues. Consequently, they may
(32). So, abnormally high rates of glucose uptake and oxidation interfere with glucose cellular uptake, as recently review in rela-
must exist in cancer cells in order to support their increased tion to glucose intestinal glucose absorption and placental glucose
energy, biosynthesis, and redox needs. Accordingly, cancer cells uptake (59). As mentioned above, the strict demand of cancer cells
possess a 20- to 30-fold increased rate of glucose cellular uptake on glucose is dependent on an increased glucose uptake capacity,
and a more than 30-fold higher glycolytic rate, when compared and for that reason inhibition of glucose cellular uptake may be a
with normal cells (33). This increased dependence of cancer cells potential strategy for cancer therapy (34–36). However, the effect
in relation to extracellular glucose levels, necessary to support of polyphenols on glucose uptake by breast cancer cells and its
high rates of glycolysis, makes interference with glucose cellular relationship with the chemopreventive/anticarcinogenic effect of
uptake, and glycolysis an attractive anticancer target (34–36). these compounds has been only scarcely studied (Table 2). These
Increased glucose cellular uptake in malignant cells has been results were recently reviewed (6).
associated with increased and deregulated expression of GLUT Gossypol (10  µM; 25  h), a polyphenolic bisnaphthalene
proteins (6). Overexpression of GLUT1 has been consistently aldehyde, markedly increased both glucose consumption, and
observed in a great variety of cancers including breast, lung, renal lactate production in MCF-7 cells (Figure  3A). It should be
cell, colorectal, and pancreas cancer (34, 37). GLUT1 is critical noted, however, that no direct measurement of glucose uptake
for glucose uptake in tumors (35, 38, 39), and is also the main was made, and so the increase in glucose consumption may be the
transporter involved in glucose cellular uptake in several breast consequence of increased glycolytic rate or increased rate of glu-
cancer cell lines (e.g., MCF-7 and MDA-MB-231) (40–42). cose oxidation not related to glycolysis (e.g., pentose phosphate
Besides GLUT1, other transporters of the GLUT family also pathway). In this context, it is important to note that gossypol has
appear to be involved in glucose cellular uptake by breast cancer been described to decrease glucose uptake in other cell types (60,
cells in culture. More specifically, expression of GLUT3 and 61, 68). Moreover, it is not apparent how the antiproliferative/

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Keating and Martel Polyphenols and Breast Cancer

Table 2 | In vitro effect of polyphenols and polyphenolic extracts on glucose uptake by breast cancer cell lines.

Compound Concentration Cell line Effect Mechanism of effect Reference

Gossypol 10 µM MCF-7 ↑ in glucose consumption and lactate Quasi-competitive inhibition (60)
production
↔ in the ratio (lactate produced)/(glucose
consumed)
Naringenin 10 µM MCF-7, T47D ↓ of basal and insulin-stimulated glucose Inhibition of MAPK-pathway (44)
uptake
Genistein 10–100 µM MCF-7, ↓ of glucose uptake Not studied (61)
MDA-MB-231
Resveratrol 150 µM T47D ↓ of glucose uptake ↓ GLUT 1 expression (62)
↓ intracellular ROS causing ↓ of HIF-1α
accumulation
Genistein, daidzein, and a IC20 = 23, 52, MCF-7, ↓ of glucose uptake Not studied (63)
soy seed extract and 166 µg/ml, MDA-MB-231
respectively
Hesperetin 50–100 µM MDA-MB-231 ↓ of basal and insulin-stimulated glucose ↓ GLUT 1 expression (48)
uptake ↓ cell membrane translocation of GLUT4

Quercetin, 1–500 µM (26 min) MCF-7, ↓ of glucose uptake Competitive, independent of PKA, PKC, (45)
epigallocatechin-3-gallate 1–100 µM (4 h) MDA-MB-231 PKG, and calcium–calmodulin intracellular
pathways
Myricetin, resveratrol 100 µM MCF-7 ↓ of glucose uptake Mixed-type inhibition (64)
genistein, kaempferol 10–100 µM
Petiveria alliacea extract 3 µg/ml 4T1 ↓ of glucose uptake Not studied (65)
Phloretin, quercetin 50–150 µM HBL100 ↓ of glucose uptake Not studied (66)
Catechin 100 µM (26 min) MCF-7 ↑ of glucose uptake (26 min) Not studied (64)
Cat:Lys complex 5 mM MCF-7 ↑ of glucose uptake (26 min) Not studied (67)
1 mM ↓ of glucose uptake (24 h)
Cat:Lys complex 5 mM MDA-MB-231 ↑ of glucose uptake (26 min) Not studied (67)
1 mM ↑ of glucose uptake (24 h)

↑, increase; ↓, decrease; ↔ no effect.

cytotoxic effect of gossypol is associated with increased glucose MCF-7 and -negative (MDA-MB-231) breast cancer cell lines
consumption (6, 62). Finally, this effect was found with a non- (70). These effects were observed with concentrations of genistein
physiological concentration of gossypol, as it is even higher than higher than the blood levels attainable with diet (even vegan diet)
gossypol blood levels found in men taking gossypol as a contra- or even with genistein pill supplements in humans (64, 66).
ceptive (0.2–0.4 µM) (69). Resveratrol (150 µM; 24 h), found in fruits such as grapes and
Naringenin (10  µM), a grapefruit flavanone, inhibited both berries, suppressed uptake of glucose and glycolysis in T47D breast
basal and insulin-stimulated glucose uptake in two breast cancer cancer cells. Resveratrol was found to reduce GLUT1 expression.
cell lines (MCF-7 and T47D cells). The reduction in insulin- Moreover, its effect on glucose uptake was concluded to result
stimulated glucose uptake was verified in both proliferating from a reduction in intracellular ROS levels, which downregulates
and growth-arrested MCF-7 cells, and was not associated with HIF-1α accumulation (63) (Figure 3C). As recently reviewed, the
changes in GLUT4 protein levels. Rather, naringenin was shown concentration of resveratrol used in this study is not achievable
to inhibit stimulation of PIP3/Akt and p44/p42 MAPK activity, in humans, even when resveratrol pill supplements are used (67,
which were induced by insulin (49) (Figure  3B). Moreover, 71), due to the low bioavailability of this compound resulting
the antiproliferative effect of naringenin was mimicked by low- from extensive metabolism (6). However, the anticancer efficacy
glucose conditions. So, it was concluded that naringenin inhibits of resveratrol may be greatly increased by avoiding the oral route,
proliferation of MCF-7 cells via impaired glucose uptake. Because as demonstrated by the observation that in vivo intraperitoneal
physiologically attainable concentrations of naringenin reduced injection of resveratrol (100 mg/kg) to mice with Lewis lung car-
insulin-stimulated glucose uptake and showed an antiprolifera- cinoma was able to reduce fluorodeoxyglucose (18F-FDG) uptake
tive effect, the authors concluded that this compound possesses by tumor cells (63).
therapeutic potential as an anticancer agent (6, 49). The flavanone hesperetin (50–100 µM; 24 h), found in citrus
The flavonoid genistein (10–100 µM; 10 min), found in soy- fruits, decreased both basal and insulin-stimulated glucose uptake
bean, reduced glucose uptake in both estrogen receptor-positive in MDA-MB-231 cells. Interestingly, the effect was distinct: the

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Keating and Martel Polyphenols and Breast Cancer

negative effect on basal glucose uptake resulted from GLUT1 The effect of genistein, daidzein, and a soy seed extract on
downregulation, whereas the negative effect on insulin-induced metabolomics of two distinct breast cancer cell lines was recently
glucose uptake was associated with impaired GLUT4 transloca- investigated (77). In MCF-7 cells, at relatively low concentrations
tion to the cell membrane (46). Again, this inhibitory effect was (2–13  µM for genistein, 2–34  µM for daidzein, and 6–68  µg/
found with hesperitin concentrations much higher than the ml for the soy seed extract), cell growth was stimulated, while
blood concentrations observed in humans taking an hesperitin- higher concentrations had an inhibitory effect. In contrast, these
rich (orange juice) diet (±0.05 μM) (65). compounds showed a concentration-dependent antiproliferative
In another study, the flavonoids quercetin and epigallocat- effect in MDA-MB-231 cells. Interestingly enough, the pro-
echin-3-gallate (EGCG) concentration-dependently inhibited proliferative effect of the compounds in MCF-7 cells was associ-
glucose uptake by MCF-7 (10–23 µM; 26 min) and MDA-MB-231 ated with an upregulation of the pentose phosphate pathway, and
(44–15 µM; 26 min) cells (50). This reduction in cellular glucose the antiproliferative effect of these isoflavones was associated
uptake was associated with a decrease in lactate production with a significant decrease in glucose uptake. In contrast, in
(Figure  3A). Quercetin and EGCG were found to be competi- MDA-MB-231 cells, the antiproliferative effect was associated
tive inhibitors of glucose uptake in MCF-7 cells and their effect with inhibition of glutamine uptake and protein biosynthesis (77).
was independent of estrogen signaling and was not mediated by Several studies indicate that the anticarcinogenic efficacy of
intracellular signaling pathways involving PKA, PKC, PKG, and polyphenols can be enhanced by combining them with com-
calcium–calmodulin. Although not so potently, a longer (4  h) pounds such as amino acids and vitamins (78). In this context, a
exposure to quercetin or EGCG caused also a decrease in glucose catechin:Lys complex (Cat:Lys) was recently tested in MCF-7 and
uptake, which was associated with an increase in GLUT1 mRNA MDA-MB-231 breast cancer cell lines. A short-term exposure
expression. Additionally, both compounds presented an antipro- (26 min) of both cell lines to Cat:Lys caused an increase in glucose
liferative and cytotoxic effect in MCF-7 cells, which was more uptake. Interestingly, a similar stimulatory effect of Cat in glucose
potent when glucose was present in the extracellular medium. uptake was observed in MCF-7 cells (75). However, when tested
So, quercetin and EGCG were concluded to inhibit basal glucose for a longer period (24 h), Cat:Lys decreases glucose uptake in
uptake and consequently lactate production in breast cancer cells MCF-7 cells and increases uptake in MDA-MB-231 cells (79).
and that these events are upstream determinants of their cytotoxic So, apparently, its antitumor effect is not related to the effect on
and antiproliferative effects (6, 50). The effective concentrations glucose uptake, because Cat:Lys showed a similar antiprolifera-
of quercetin and EGCG were higher than the blood levels found tive, cytotoxic, antimigratory, and pro-apoptotic effect on both
in humans, even after pill supplementation (72, 73). cell lines (75).
The inhibitory effect of quercetin on glucose uptake by Finally, an extract of Petiveria alliacea (3 µg/ml; 48 h), known
breast cancer cells was investigated in a later study. In this work, to contain flavonoids such as myricetin, was found to decrease
quercetin and phloretin were found to inhibit the growth of four glucose uptake and lactate production in the 4T1 breast cell line.
distinct breast cancer cell lines (MCF-7, MDA-MB-231, HBL100, However, no direct measurement of glucose uptake was done;
and BT549 cell lines). When investigated in more detail, it was rather, glucose levels in supernatant were measured (9).
concluded that both polyphenols (50–150  µM; 24  h) decrease So, for many of the investigated polyphenols, an inhibitory
glucose cellular uptake and lactate production in the HBL100 cell effect in relation to glucose uptake by breast cancer cells was found.
line, although no such effect was demonstrated in the MCF-7 cell Moreover, for some polyphenols, their anticancer effect was shown
line (74). The distinct effect of quercetin upon glucose uptake in to be dependent on inhibition of glucose cellular uptake (6). The
MCF-7 cells between this work and the work by Moreira et al. (50) fact that, for kaempferol, inhibition of lactate cellular uptake was
may be related to distinct times of exposure to this compound also demonstrated, raises the hypothesis that other polyphenolic
(4 vs 24 h). It should also be mentioned that the later work did compounds may also interfere with this mechanism. Compounds
not measure glucose uptake, but rather glucose remaining in the inhibiting both glucose and lactate uptake are very interesting in
culture medium, and this parameter depends not only on glucose the context of cancer therapy, because they will deplete cancer
uptake but also on glucose metabolic rates. cells of their two major energy substrates (6).
A recent work showed that exposure to several polyphenols
(myricetin, genistein, resveratrol, and kaempferol) reduced glu-
cose uptake by MCF-7 cells (Figure 3A). Kaempferol was found EFFECT OF POLYPHENOLS ON
to be the most potent inhibitor, with an IC50 of 4 µM. Kaempferol GLYCOLYSIS IN BREAST CANCER CELLS
(30  µM) was concluded to inhibit GLUT1-mediated glucose
uptake, as it decreased glucose uptake and downregulated GLUT1 As mentioned above, cancer cells are dependent on high rates of
mRNA expression. Interestingly enough, low-extracellular glu- glycolysis and lactate production. So, the enzymes contributing
cose mimicked the antiproliferative and cytotoxic properties of to glycolysis may represent an attractive target for cancer therapy.
kaempferol, and high-extracellular glucose conditions prevented Nevertheless, only a few studies have described the ability of
the effect of kaempferol. This clearly showed that inhibition of polyphenols to inhibit the glycolytic pathway in breast cancer
glucose cellular uptake mediates the anticancer effect of kaemp- cells, independently from inhibition of glucose cellular uptake
ferol in MCF-7 cells (6, 75). The concentrations found to be (Table 3).
effective are higher than the blood levels of kaempferol attainable Luteolin (50–100 µM; 10 min), found in oregano and celery
from diet in humans (76). seed, was found to decrease the glycolytic flux in two distinct

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Keating and Martel Polyphenols and Breast Cancer

Table 3 | In vitro effect of polyphenols on glycolysis in breast cancer cell lines. flux several fold in order to obtain the necessary amount of ATP
Compound Concentration Cell line Effect Reference (see above), this increases the level of MG to toxic concentrations.
Consequently, most cancer cells show increased expression of
Luteolin 50–100 µM 4T1, ↓ of glycolytic (72) GLO1 (80). Interestingly enough, several polyphenols (curcumin,
(10 min) MCF-7 flux
quercetin, myricetin, kaempferol, luteolin, and rutin) were found
Resveratrol IC50 = 15 µM MCF-7 ↓ of PFK (73)
to inhibit GLO1 specific activity (Figure 3D). Of these, curcumin
1,2,3,4,6-penta-O- 40 µM (24 h) MDA- ↓ of PC, (74) was found to be the most potent (Ki  =  5  μM). The authors
galloyl-β-d-glucose MB-231 ACYP2,
presented evidence that inhibition of GLO1 by curcumin may
ALDH3B1
result in non-tolerable levels of MGO and GSH, which, in turn,
↑, increase; ↓, decrease. may lead to depletion of cellular ATP and GSH, accounting to
the antitumor efficacy of curcumin in several cell lines, including
breast cancer cell lines, 4T1 and MCF-7 cells. Interestingly, two breast cancer cell lines (JIMT-1 and MDA-MB-231) (81). Of
enough, this effect was observed only under hypoxic conditions, note, curcumin blood levels in humans are lower than 1 µM, even
and was not associated with inhibition of glucose cellular uptake. after curcumin pill supplementation (82).
Although the concentrations of luteolin effective in reducing Uridine diphosphate (UDP)-glucose dehydrogenase (UGDH)
glycolytic flux were much higher than the diet-attainable con- catalyzes the oxidation of UDP-glucose to yield UDP-glucuronic
centration in humans (76), combination of luteolin (100  mg/ acid, a precursor for the biosynthesis of glycosaminoglycans and
kg) with doxorubicin had superior efficacy, and lesser toxicity proteoglycans (83). Increases in UDP-glucuronic acid levels can
compared with doxorubicin alone, in relation to decrease in cause excessive production of proteoglycans, compounds that
tumor size and weight loss, in mice. So, it was concluded that have been implicated in the progression of breast cancers (83).
luteolin, as a glycolytic inhibitor, might be a new adjuvant agent Moreover, upregulation of UGDH by estrogen and androgens is
for chemotherapy (10). known to be present in estrogen-responsive breast cancer cells
6-Phosphofructo-1-kinase-1 (PFK) is a critical glycolytic (84). In this context, gallic acid and quercetin (300  µM; 24  h)
enzyme, and its activity is directly correlated with cellular glu- were found to decrease the specific activity of UGDH at the post-
cose consumption (11). Gomez et  al. showed that resveratrol translational level (Figure 3E). Gallic acid appears to be a non-
(1–100 µM; 24 h) causes a decrease in cell viability, glucose con- competitive inhibitor of the enzyme, whereas quercetin appears
sumption, and ATP content in MCF-7 cells, and that these effects to be a competitive inhibitor. Because these two compounds
are correlated with PFK inhibition. Furthermore, they showed inhibited the proliferation of MCF-7 human breast cancer cells,
that resveratrol directly inhibits PFK (Figure  3C), causing a it was concluded that gallic acid and quercetin are effective inhibi-
decrease in both affinity and Vmax, by promoting the dissociation tors of UGDH that exert strong antiproliferative activity in breast
of the enzyme from fully active tetramers into less active dimers cancer cells (85).
and that its effect is exacerbated by known negative regulators of
the enzyme (such as ATP and citrate) and prevented by positive CONCLUSION AND FUTURE
modulators (such as fructose-2,6-bisphosphate and ADP) (11). PERSPECTIVES
In summary, resveratrol was concluded to cause direct inhibition
of PFK activity, therefore disrupting glucose metabolism and Despite the high-survival rate in breast cancer patients and
reducing breast cancer cell viability (11). Of relevance, the lowest the availability of well-designed and effective therapeutic
concentration of resveratrol found to be effective (1 µM) is attain- strategies, especially for hormone receptor or HER2-positive
able in human blood after pill supplementation (71). breast cancer, there is still the need for more drug research
Besides glycolytic enzymes, some polyphenols were found to particularly regarding triple-negative breast cancer, because of
interfere with other enzymes participating in glucose utilization its unresponsiveness to hormone or anti-HER2 therapy. In fact,
by cancer cells, as shown next. drug discovery lies in the list of cancer research priorities in the
1,2,3,4,6-penta-O-galloyl-beta-d-glucose (PGG), a polyphe- United States set by the Lancet Oncology Commission in the
nolic compound isolated from Rhus chinensis, is known to have end of 2017 (4).
antitumor, antiangiogenic, and antidiabetic activities. Recently, Cancer cell energy metabolism is an important target for
this compound was shown (by microarray data and real-time improved therapeutic strategies. In this regard, polyphenols may
RT-PCR) to cause a significant downregulation of genes add an important contribution for anticancer therapy. Indeed,
involved in pyruvate metabolism, namely pyruvate carboxylase, many of these phytochemicals have been shown to regulate redox
acylphosphatase, and ALDH3B1 (aldehyde dehydrogenase). balance, cell proliferation, apoptosis, autophagy, angiogenesis,
These findings led the authors to suggest the potential of PGG inflammation, cell receptor and transcription factor expression,
as anticancer agent for breast cancer cells by targeting cancer hormone synthesis, microbiota composition, and epigenetic
metabolism genes (12). mechanisms, all of which may underlie carcinogenesis and tumor
Glyoxalase-1 (GLO1) is a ubiquitous cellular enzyme that progression. In addition, as exposed in this review, polyphenols
participates in the detoxification of methylglyoxal (MG), a cyto- from almost all classes (Figure 2) have been described to target
toxic by-product of glycolysis (80). The expression of GLO1 is glucose uptake or metabolism in breast cancer cells.
correlated to the flux of glucose being oxidized in the glycolytic The studied mechanisms underlying glucose uptake inhibi-
pathway, and because cancer cells must increase their glycolytic tion in breast cancer cells are also diverse, ranging from direct

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Keating and Martel Polyphenols and Breast Cancer

functional effect upon the transporter, inhibition of transporter cancer. This same formulation rich in EGCG has been found
gene expression, impairment of membrane translocation pro- to be well-tolerated in another trial with patients with Barrett’s
cesses, and redox balance modulation with implications in the esophagus (90).
accumulation of a transcription factor (Table  2). The effect of Another important point relates to the fact that the effect of
polyphenols upon glycolysis is less studied, but seems to involve polyphenols in normal breast cells has not been addressed. So, it is
direct inhibition of glycolytic enzymes and inhibition of enzyme reasonable to question whether it is appropriate to non-selectively
gene expression. target molecules expressed both in normal and in cancer cells.
An important point concerns the fact that, for most of the However, we know that cancer cells are likely to suffer more
polyphenols presented above, their inhibitory effect upon glu- severely than normal cells from glucose deprivation, given their
cose transport or metabolism was found, in  vitro, with higher extremely higher dependence on high amounts of glucose. In this
than physiological human blood concentrations. So, the in vivo context, it should also be considered that compounds targeting
efficacy of these compounds in inhibiting glucose transport and upstream players in glucose metabolism (GLUTs or enzymes in
metabolism, as contributing to their antitumor effect, should be the first step of glycolysis) are likely to induce more adverse side
addressed. effects, given that this inhibition will be less glycolysis-specific,
To date, clinical trials in cancer patients using polyphenols when compared with compounds targeting downstream players.
to ensure their safety and/or efficacy are still largely lacking. One example of this is the failure of 2-DG, an inhibitor of GLUT1,
Nevertheless, some studies have been conducted; some of them as a chemotherapeutic agent (7). So, research on the effects of
had disappointing results, but some deserve further studies. For polyphenols on glucose metabolism of (breast) cancer cells
example, clinical studies using gossypol have shown that this poly- should be fostered in the near future.
phenol seems to be safe; however, it presented a negligible anti-
tumor effect in advanced breast cancer (86). Moreover, although AUTHOR CONTRIBUTIONS
soy isoflavone supplementation have proven to be uneffective in
breast cancer prevention (87), a phase II placebo-controlled, ran- EK and FM equally contributed to the manuscript conception
domized, double-blind clinical trial in prostate cancer patients and writing.
evidenced genistein as a well-tolerated chemopreventive agent
(88, 89). To our knowledge, no trials have been performed with FUNDING
genistein in breast cancer patients, and this issue deserves further
attention. Finally, EGCG has been recently tested in a phase II This work was funded by Instituto de Investigação e Inovação
randomized, double-blind, presurgical trial with bladder cancer em Saúde, Universidade do Porto, Portugal (UID/BIM/04293/
patients. ECGC was detected in plasma, urine, and bladder tissue 2013), and by FEDER through the operation POCI-01-0145-
in a dose-dependent profile, after administration of a green tea FEDER-007746 funded by the Programa Operacional
polyphenol formulation rich in this polyphenol, and it was found Competitividade e Internacionalização—COMPETE2020 and
to modulate tissue biomarkers of proliferation and apoptosis by National Funds through FCT—Fundação para a Ciência e
(86). This trial indicates that ECGC could be a promising natural a Tecnologia within CINTESIS, R&D Unit (reference UID/IC/
compound for a clinical trial in cancer patients, including breast 4255/2013).

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Conflict of Interest Statement: The authors declare that no competing financial
doi:10.18632/oncotarget.4499
interests exist and that they have no conflict of interest.
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76. Cao J, Zhang Y, Chen W, Zhao X. The relationship between fasting plasma copyright owner are credited and that the original publication in this journal is cited,
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Frontiers in Nutrition  |  www.frontiersin.org 11 April 2018 | Volume 5 | Article 25